Is PTGS2 p.Pro92Thr (c.274C>A) pathogenic?

PTGS2 p.Pro92Thr (c.274C>A) is classified Uncertain significance in PTGS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.00333%, amr).

How common is PTGS2 p.Pro92Thr (c.274C>A) in the general population?

PTGS2 p.Pro92Thr (c.274C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PTGS2 p.Pro92Thr (c.274C>A)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

PTGS2 p.Pro92Thr

c.274C>A · VCV4147190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 1,917 bp · p 0.027 · regional, not allelic
Overall
CADD	17.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000496% 8/1,614,038 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-American	0.00133%	74,936
European (non-Finnish)	0.000254%	393,342

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PTGS2
Protein: p.Pro92Thr
Coding: c.274C>A
MANE Select: NM_000963
Type: single nucleotide variant
Location: chr1:186679097 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 93.37 · 7 PDB
Residue 92: a disulfide bond; an α-helix

Full PTGS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTGS2 p.Arg585= Benign ★★ same type
PTGS2 p.Asp300= Benign ★★ same type
PTGS2 p.His403= Benign ★★ same type
PTGS2 p.Ala436Ser Uncertain significance ★ ⚠ same type
PTGS2 p.Ala475Thr Uncertain significance ★ ⚠ same type
PTGS2 p.Ala529Ser Uncertain significance ★ ⚠ same type
PTGS2 p.Ala529Val Uncertain significance ★ ⚠ same type
PTGS2 p.Ala581Gly Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ptgs2-p-pro92thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown